REGγ-mediated Barrier Disruption and NF-κB Activation Aggravates Intestinal Inflammation in Necrotizing Enterocolitis

Ya Li; Deng Pan; Huifeng Liu; Wenya Xie; Xiaoyong Li; Xin Mu; Li Chen; Min Yang; Xianliang Wang; Xianxiao Li; Jianhui Li; Bianhong Zhang; Fangxia Guan; Faisal Aziz; Jingyu Cao; Xiangzhan Zhu

doi:10.1007/s10753-024-02203-2

REGγ-mediated Barrier Disruption and NF-κB Activation Aggravates Intestinal Inflammation in Necrotizing Enterocolitis

Inflammation. 2024 Dec 10. doi: 10.1007/s10753-024-02203-2. Online ahead of print.

Authors

Ya Li^#^{1

2

3}, Deng Pan^#⁴, Huifeng Liu⁴, Wenya Xie⁴, Xiaoyong Li⁴, Xin Mu⁴, Li Chen⁴, Min Yang⁴, Xianliang Wang⁴, Xianxiao Li⁵, Jianhui Li⁶, Bianhong Zhang⁷, Fangxia Guan⁸, Faisal Aziz⁹, Jingyu Cao^{10

11}, Xiangzhan Zhu^{4

8

12

10

11}

Affiliations

¹ Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Zhengzhou, China.
² Henan Provincial Outstanding Overseas Scientists Chronic Liver Injury Workshop, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Henan Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Department of Neonatal Surgery, Children's Hospital Affiliated of Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.
⁵ Accident and Emergency Care Department, Henan Province Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
⁶ Department of Pathology, Xuchang Central Hospital Affiliated to Henan University of Science and Technology, Xuchang, China.
⁷ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
⁸ School of Life Sciences, Zhengzhou University, Zhengzhou, China.
⁹ The Hormel Institute, University of Minnesota, Austin, MN, USA.
¹⁰ Henan Province Children's Disease Clinical Medical Research Center, Children's Hospital Affiliated of Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.
¹¹ Institute of Pediatric Medicine, Children's Hospital Affiliated of Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.
¹² School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

^# Contributed equally.

PMID: 39653983
DOI: 10.1007/s10753-024-02203-2

Abstract

Necrotizing enterocolitis (NEC) stands as the most prevalent and severe gastrointestinal ailment affecting premature newborns, particularly those with extremely low birth weights. Intestinal barrier dysfunction emerges as a crucial factor in NEC's pathogenesis. REGγ predominantly manifests in the intestinal epithelium and has shown to regulate experimental colitis. However, the potential correlation between REGγ and NEC remains ambiguous. This study reveals that REGγ is notably overexpressed in both human and murine NEC samples. REGγ-deficient mice displayed improvements in intestinal mucosal inflammation and reduced NEC severity. Additionally, REGγ deficiency notably lowered the expression of phosphorylated transcription factor p65 and inflammatory factors in intestinal epithelial cells of NEC-afflicted mice. REGγ exacerbates the local inflammation by triggering the degradation of IκBɛ, a negative regulator of NFκB. Clinically, REGγ and p65 expression levels exhibit a positive correlation in NEC specimens. Moreover, pre-treatment of mice with a p65 inhibitor effectively suppressed the expression of inflammatory mediators and alleviated REGγ-mediated NEC development. These findings underscore that abnormal upregulation of REGγ triggers NEC development by enhancing NF-κB activity and exacerbating epithelial barrier dysfunction. Thus, novel therapeutic approaches targeting REGγ inhibition may offer enhanced treatment for NEC.

Keywords: Gut permeability; Inflammation; NF-κB; Necrotizing enterocolitis; REGγ.